CA2381875A1 - Multioligoanilinated fullerenes - Google Patents

Abstract

A compound, of the following formula:

Description

Multioligoanilinated Fullerenes BACKGROUND OF THE INVENTION
Free radicals have been shown to inhibit tumor growth by causing oxidative damage to lipids, proteins, and nucleic acids of the tumor cells. In clinical practice, a photo-sensitizes is first delivered to a tumor site and then activated by irradiation to generate free radicals, thus inhibiting tumor growth. Among known photo-sensitizers, Photofrin II has recently been approved by the U.S. Food and Drug Administration. Preparation of Photofrin II is tedious.
Fullerenes are conjugated olefins of a closed cage structure. When photo-excited, they are capable of transforming molecular oxygen into singlet oxygen and then the related free radicals, such as superoxide free radicals, i.e., O2~'. However, fullerenes have low bioavailability and must be chemically modified before they can be tested for their efficacy, if any, as photo-sensitizers in treating tumor.
SUMMARY OF THE INVENTION
One aspect of this invention relates to multioligoanilinated fullerenes (MOAFs) of the ~ 5 following formula:
O CT)q CS'Ip-FI~C'~C-~G-F2~A)a K~c ~n~
m In this formula, p and each q, independently, is an integer of 0-20; each a is an integer of 1-8;
each b is 0 or l; each c is an integer of 1-20, provided that when b is 0, c is 1; each n is 1 or 2; m is an integer of 1-20; Fl and each F2, independently, is a C6o-sb or C7oa6 fullerene, 2o preferably a C6o-66 or Coo fullerene; each of S and T, independently, is -OH, -NHz, -NHR, or -SH, wherein R is C1_3o alkyl; each A, independently, is an oligoaniline, the term "oligoaniline" referring to a linear chemical species, the backbone of which consists of 2-12 aniline units; each nitrogen atom of the oligoaniline is optionally substituted with -Z, -CHz-CO-OH, -CHZ-CO-O-Z, -CHZ-CO-S-Z, -CHz-CO-NH2, or -CH2-CO-NH-Z; and each 25 benzene ring is optionally substituted with -O-Z, -S-Z, -NH-Z; Z being -E-D, wherein E is _. ..._.- _ . ,._...... _."~.»~..... ..___.

-R-, -R-Ar-, -Ar-R-, or -Ar-; and D is -OH, -SH, -NHZ, -NHOH, -S03H, -OS03H, -COzH, -CONHz, -CH-(NHz)-COzH, -P(OH)3, -PO(OH)z, -O-PO(OH)2, -O-PO(OH)-O-PO(OH)z, -O-PO(O-)-O-CHZCHzNH3+, -glycoside, -OCH3, -OCHz(CHOH)4-CHZOH, -OCHz(CHOH)z-CH20H, -C6H3(OH)z, -NH3+, -N+HzRb, -N~'~HR»RG, or -N+RbR~Rd, R being Ci_3o alkyl, each s of Rb, Rz, and R~, independently, being C~_ZO alkyl; and Ar being aryl; each K, independently, is -H, -[N(X)-C6Ha]1_3-NHz, -[N(X)-C6Ha]1-3-NH-C(-S)-SH, -[N(X)-C6H4)1.s-N=CH-Ar-SH, -[N(X)-C6H4J1.3-NH-CO-Ar-SH, wherein X is -H, -Z, -CHz-CO-OH, -CHz-CO-O-Z, -CHz-CO-S-Z, -CH2-CO-NH2, -CHZ-CO-NH-Z; and Ar is aryl; each C~ independently, is -O-B-R-O-, -NH-B-R-NH-, -O-B-R-NH-, -NH-B-R-O-, -O-B-R-S-, -NH-B-R-S-, wherein R is C,_3o alkyl; B, independently, is -Rl-O-[Si(CH3)z-O-]1_100, C1-zooo alkyl, C6.~o aryl, C7_6o alkylaryl, C~_6o arylalkyl, (Cl_3o alkyl ether)1_1o0, (C6-ao aryl ether)1_looa (C~-so alkylaryl ether)1_1o0~ (C7-6o arylalkyl ether)1_1o0, (C1-3o alkyl thioether)1_1o0~ (C6-ao aryl thioether)1_1o0, (C7-bo alkylaryl thioether),_loo, (C~~o arylalkyl thioether)1_ioo, (Cz-so alkyl ester)1_1o0, (C~-bo aryl ester)1_too~
(C8_7o alkylaryl ester)1_1o0, (Csao arylalkyl ester)1_1o0, -Rl-CO-O-(C1_3o alkyl ether)1_1o0~ -Rl-~s CO-O-(C6~ aryl ether)1_1o0, -Rl-CO-O-(C7_bo alkylaryl ether)1_1o0, -Rl-CO-O-(C~_~ arylalkyl ether)1_lo0, (Ca-so amyl urethane)1_100, (C1a-so aryl urethane)1_100, (C,o.so alkylaryl urethane)1_ loo (Clo-so ar'Ylalkyl urethane)1_1o0~ (Cs-so amyl urea)t_loo~ (Cia-bo ~'Yl ~'ea)t_loo, (Clo-so alkylaryl urea)t_loo, (Cto-xo arylalkyl urea)1_~o0, (Cz-so alkyl amide)~_,oo, (C~-bo aryl amide)I_loo~
(Caao a~Yl~'Yl amide)1_1o0, (C8-7o arYla~Yl amide)1_1o0, (C3-30 a~kYl ~Ydride)1_1o0, (Ca-so aryl 2o anhydride)1_lo0, (C9_6o alkylaryl anhydride)1_1o0, (C9-60 arylalkyl anhydride)1_1o0, (Cz-3o alkyl carbonate)1_t~, (C7_so aryl carbonate)t_too~ (C8-so alkylaryl carbonate)1_too, (Ca-6o arylalkyl carbonate)1_1o0, -Rl-O-CO-NH-(Rz or Ar-Rz-Ar)-NH-CO-O-(C1-so alkyl ether, C6~o aryl ether, C7_6o alkylaryl ether, or C~_bo arylalkyl ether)l.loo, -Rl-O-CO-NH-(Rz or Ar-R2-Ar)-NH-CO-O-(C2_so alkyl ester, C7_6o aryl ester, C8_7o alkylaryl ester, or CB.~o arylalkyl ester)1-loo, -R1-0-25 CO-NH-(Rz orAr-Rz-Ar)-NH-CO-O-(C,_3o alkyl ether, C6~o aryl ether, C~_bo alkylaryl ether, or C7.bo arylalkyl ether)1_loo-CO-NH-(Rz or Ar-Rz-Ar)-NH-CO-O-, -Rl-O-CO-NH-(Rz or Ar-Rz-Ar)-NH-CO-O-(Cz_so alkyl ester, C~_6o aryl ester, C$_~o alkylaryl ester, or C8_7o arylalkyl ester)1_loo-R3-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -Rl-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(Cl_3o alkyl ether, Cs~o aryl ether, C~_6o alkylaryl ether, or C~~o arylalkyl ether)1_ 30 loo, -Rl-NH-CO-NH-(RZ or Ar-R2-Ar)-NH-CO-(Cz_so alkyl ester, C7.~ aryl ester, C8_7o alkylaryl ester, or CB.~o arylalkyl ester)1_1o0, -RmNH-CO-NH-(Rz or Ar-Rz-Ar)-NH-CO-O-___. . ~.w..... ._... .
__.

(Ci-3o alkyl ether, C6.~o aryl ether, C~_6o alkylaryl ether, or C~_6o arylalkyl ether)1_~oo-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-NH-CO-NH-(R2 or Ar-RZ-Ar)-NH-CO-O-(CZ_so alkyl ester, C~_6o aryl ester, C8_~o alkylaryl ester, or C8_~o arylalkyl ester)1_ioo-R30-CO-NH-(R2 or Ar-RZ-Ar)-NH-CO-O-, -Rl-O-CO-NH-(RZ or Ar-RZ-Ar)-NH-CO-NH-(CZ_so alkyl amide, C~~o aryl amide, C8_~o alkylaryl amide, or Cg_7o arylalkyl amide)I_loo, or -Rl-NH-CO-NH-(RZ or Ar-RZ-Ar)-NH-CO-NH-(CZ_so alkyl amide, C~_6o aryl amide, C8_~o alkylaryl amide, or C8_~o arylalkyl amide)1_1o0; wherein each of Rl, Rz, and R3, independently, is Ci_3o alkyl; and Ar is aryl.
Also within the scope of this invention are pharmaceutically acceptable salts of the MOAFs described above. Such a salt can be formed between a negatively charged ionic group (e.g., sulfonate or carbonate) in an MOAF and a positively charged counterion (e.g., a sodium ion). Likewise, a positively charged ionic group (e.g., ammonium) in an MOAF
can also form a salt with a negatively charged counterion (e.g., chloride).
One subset of the MOAF's of this invention are featured by that a is an integer of 3-6.
Another subset of the MOAFs are featured by that b is 1, or b is 0 and c is 1.
Still another subset of the MOAFs are featured by that n is 2. Yet stilled another subset of the MOAFs are featured by that A is tetraaniline, optionally substituted at nitrogen atoms with Z; E is -R- or -R-Ar-; and D is -OH, -SH, -NH2, -NHOH, -SO3H, -OS03H, -COZH, -CONHz, -P(OH)3, -PO(OH)2, -O-PO(OH)2, -O-PO(OH)-O-PO(OH)2, or -NH3+.
2o Another aspect of this invention relates to a pharmaceutical composition which includes a pharmaceutically effective amount of an MOAF described above and a pharmaceutically acceptable carrier. Examples of such a carrier include water, colloidal silica oxide, magnesium sterate, and cellulose.
An MOAF of this invention can be used as a photodynamic therapeutic agent to inhibit growth, including causing death, of tumor cells in a tumor site.
Accordingly, this invention also relates to use of an MOAF for the manufacture of a medicament for this application.
Details of several embodiments of this invention are set forth in the accompanying description below. Other features, objects, and advantages of this invention will be apparent 3o from the description and from the claims.

....._. _m.a-,~..,.,.~...".~.._ _ DETAILED DESCRIPTION OF THE INVENTION
An MOAF of this invention can be synthesized by methods well known in the art.
For instance, a fullerene can be first converted to a fullerene carboxylate by reacting it with a carboxylating agent such as diethyl bromomalonate. The fullerene carboxylate derivative is then oligoanilinated and, optionally, modified at the introduced oligoaniline moieties to generate ionic groups, e.g., alkylsulfonyl. Another suitable moiety, such as fullerene, can be introduced by further modifying one of the ionic groups. Each fullerene moiety can also be modified for introduction of hydrophilic groups, e.g., hydroxy, by reacting with dilute NaOH
in the presence of a phase-transfer catalyst and aerated oxygen.
An effective amount of MOAF thus prepared can be formulated with a pharmaceutically acceptable carrier to form a pharmaceutical composition before being administered to a subject in need of tumor treatment. "An effective amount"
refers to the amount of the MOAF which is required to confer therapeutic effect on the treated subject.
The interrelationship of dosages for animals and humans (based on milligrams per square ~ 5 meter of body surface) is described by Freireich et al., Cancer Chemother.
Rep. 1966, 50, 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537.
Effective doses will also vary, as recognized by those skilled in the art, depending on the route of administration, the excipient usage, the distance of tumor from the skin surface, the 2o source of the irradiation, and the optional co-usage with other therapeutic treatments including use of other anti-tumor compounds. Examples of pharmaceuticahy acceptable carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and D&C Yellow # 10.
The pharmaceutical composition may be administered via a parenteral route, e.g., 25 topically, intraperitoneally, and intravenously. Examples of parenteral dosage forms include an active compound dissolved in phosphate buffer solution (PBS), or admixed with any other pharmaceutically acceptable carrier. Solubilizing agents, such as cyclodextrins, or other solubilizing agents well known to those familiar with the art, can also be included in the pharmaceutical composition.
so The invention also relates to the use of an MOAF of this invention or a composition containing thereof for the manufacture of a medicament for tumor. More specifically, the MOAF is administered to the tumor site and then irradiated with laser or other light sources, e.g., fluorescence or X-ray. The irradiation can be of a wavelength of 400-1000 nm and an energy intensity of 10-300 J/cm~, and the irradiation time can be 10-200 minutes. Upon irradiation, superoxide radicals are generated, which in turn attack and inhibit the growth of tumor cells.
An in vitro inhibition assay can be used to preliminarily evaluate an MOAF's ability to inhibit the growth of tumor cells. For example, an MOAF solution can be added to a pre-incubated cell suspension. Subsequently, the cell suspension is irradiated with fluorescence light, followed by further incubation. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide solution is then added to the cell suspension to react with mitochrondrial dehydrogenase to form formazon, which is extracted with dimethyl sulfoxide (DMSO). The DMSO extract solution is immediately used for optical measurement to determine the quantity of the formazon, which correlates with the quantity of dehydrogenase or the relative number of the living cells.
~5 The MOAFs of this invention, which have been preliminarily evaluated, can be further screened for their efficacy by an in vivo inhibition assay using tumor-bearing mice.
For example, each tumor-bearing mouse can be first administered with an MOAF
to be tested in PBS close to the tumor site. The mouse is then kept in the dark while the MOAF is circulated to the tumor site. The tumor site is exposed by removing the hair on and around it 2o and then irradiated with a laser beam or other light source. The growth of the tumor in the mouse is then examined at different time intervals. The inhibitory effect is evaluated by measuring the mouse's body weights and tumor volumes. After the mouse is sacrificed, the body weight and various organ weights are also measured, and blood samples are withdrawn for biochemistry and hematology analyses. All such data can be used to evaluate the efficacy 25 of the MOAF to treat tumor.
Without further elaboration, it is believed that one skilled in the art, based on the description herein, can utilize the present invention to its fullest extent.
All publications recited herein are hereby incorporated by reference in their entirety. The following specific examples, which describe synthesis and biological testing of several MOAFs of this 3o invention, are therefore to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Example 1 (1) Synthesis of diethylmalonate monoadduct of C6o (F2E) A mixture of C6o, diethyl bromomalonate (1.0 equiv.), 9,10-dimethylanthracene (DMA, 1.2 equiv.), and diazabicyclo[5.4.0]undec-7-ene (DBU, 1.2 equiv.) in toluene was s used in an ethyl malonate-addition reaction on C6o at ambient temperature for 10 hours. See Hirsch et al. ,I. Am. Chem. Soc.,1994, 116, 9385. The product mixture thus obtained was subjected to repeated SiOz chromatographic separation by using toluene-hexane (1:2) as the eluent. One thin layer chromatography (TLC, Rf 0.75) fraction, corresponding to the product, C6o-[C(COZEt)2], were isolated in a 54% yield.
m/z (relative intensity, %): 879 (n=1), and 720 (C6o).
IR (KBr) u,~,ax: 3392 (br), 2930 (C-H), 2859, 1656, 1596, 1504 (s), 1316, 1170, 1115, 835, 751, 697, and 508 cm 1.
1H-NMR 8: 6.50-7.30 (m).
(2) Synthesis of dodecaethylhexakis(methano)[60]fullerene dodecacarboxylate (F12E) ~s and decaethylpentakis(methano)[60[fullerene decacarboxylate (FlOE).
A mixture of C6o, diethyl bromomalonate (6.0 equiv.), 9,10-dimethoxyanthracene (DMOA, 10 equiv.), and DBU (7.0 equiv.) in toluene was stirred at ambient temperature for 12 hours. Into the reaction flask., additional diethyl bromomalonate (4.0 equiv.) and DBU
(5.0 equiv.) were charged. The reaction was allowed to continue for 24 hours.
See Hirsch et 2o al. Angew. Chem. Int. Ed. Engl. 1995, 34, 1607. The product mixture thus obtained was subjected to repeated Si02 chromatographic separation by using THF-toluene (1:9) as the eluent. Three thin layer chromatography (TLC) fractions, corresponding to there products, Cbo-[C(COZEt)z]" (n=3, 4, and 5, respectively), were isolated and identified by their molecular ion mass as Cbo-malonate adducts: F8E (n=4, Rf 0.62, m/z 1353, 7.5%
yield), F10E
25 (n=5, Rf 0.53, mlz 1511, 21% yield), and F12E (n=6, Rf 0.44, mlz 1669, 56%
yield).
FBE:
m/z (relative intensity, %): 1353 (100, n=4), 1195 (9.9, n=3), 1037 (5.7, n=2), 878 (4.2, n=1), and 720 (38.8).

IR (KBr) u,r,a,~: 3441 (br), 2983 (C-H), 2938, 2907, 2874, 1747 (s, ester carbonyl), 1465, 1446, 1391, 1369, 1299, 1235 (s), 1180 (shoulder), 1108, 1065, 1023, 861, 815, 737, 708, and 528 cm 1.
LTV-Vis (1.0 x 10'5 M in THF) ~,n,ax: 294 and 469 nm.
s F10E:
m/z (relative intensity, %): 1511 (100, n=5), 1353 (16.9, n=4), 1195 (13.7, n=3), 1037 (11.2, n=2), 878 (8.1, n=1), and 720 (44.7).
IR (KBr) u",a,~: 3454 (br), 2983 (C-H), 2939, 2908, 2875, 1747 (s, ester carbonyl), 1466, 1447, 1392, 1370, 1297, 1233 (s), 1179 (shoulder), 1112, 1098, 1073, 1023, 859, 817, 737, 708, and 525 cm't.
L1V-Vis (THF, 1.0 x 10'5 M) ~.",aX: 286 and 444 nm.
~3C NMR (CDC13, major brown-red regioisomer) 8: 41.5, 43.7, 46.8, 47.2, 48.9, 49.8, 67.5, 68.5 (2C), 68.9, 69.3, 69.5, 69.6, 70.6, 70.9, 71.2, 72.1, 134.0, 135.1, 136.9, 137.8, 138.1, 139.2, 139.4, 139.7, 139.8, 140.5, 140.6, 140.7, 140,8, 140.9, 141.24, 141.23, 141.3, 141.4, ~5 141.8, 141.9, 142.0, 142.1, 142.6, 142.9, 143.0, 143.6, 143.7, 143.8, 144.0, 144.2, 144.3, 144.36, 144.39 (2C), 144.7, 144.8, 145.2, 145.4, 145.4, 145.6, 145.8, 145.1, 146.2, 146.9, 147.2, 147.4, 147.6, 147.7, and 147.8 (2C).
F12E:
m/z (relative intensity, %): 1669 (100, n=6), 1511 (15.5, n=5), 1353 (10.9, n=4), 1195 (8.8, 2o n=3), 1037 (4.3, n=2), 879 (4.6, n=1), and 720 (53.7);
IR (KBr) u",~,~: 3455 (br), 2985, 2939 (C-H), 2910, 2875, 1747 (s, ester carbonyl), 1467, 1448, 1393, 1370, 1297, 1241 (s;), 1223 (s), 1177 (shoulder), 1096, 1080, 1020, 859, 815, 715, and 527 cm 1.
LN-Vis (1.0 x 10-5 M in THF) ~,~: 278 and 337 nm.
25 1H-NMR 8: 1.1?-1.34 (m, 36H), 4.31-4.41 (m, 24H).
13C NMR (CDCl3, yellow regioisomer) ~: 45.3, 69.0, 141.1, 145.7, and 163.8.

13C NMR (CDC13, orange-red regioisomer) &. 64.2, 66.5, 66.9, 68.2, 68.3, 68.4, 68.8, 69.5, 69.8, 70.0, 70.4, 70.7, 130.9, 132.6, 134.7, 135.6, 137.2, 137.8, 138.1, 138.7, 139.2, 139.4, 139.7, 139.8, 140.2, 140.9, 141.3, 141.4, 141.6, 141.9 (4C), 142.0 (2C), 142.1, 142.2, 142.4, 142.5, 142.7, 143.9, 144.2, 144.4, 144.5, 144.8, 145.0, 145.2 (2C), 145.5 (2C), 145.6 (2C), 145.6 (3C), 145.9, 146.0, 146.1, 146.4, 147.7, 161.3, 162.9, 163.1, 163.2, 163.4, 163.64, 163.65, 163.7, 163.85 (2C), 163.9, and 164Ø
(3) Synthesis of fullerene bis(hexadecaaniline) adduct (F2A16).
180 mg F2E (0.2 mmol) in 10.0 mL DMSO and 0.5 mL THF were mixed in a dry flask equipped with a stirring bar and a condenser under N2. To the solution were then sequentially added 0.6 mL DBU (4.0 mmol), and 660 rng hexadecaaniline (A16) in the emeraldine base form (0.45 mmol) in 5.0 mL DMSO. The mixture thus obtained was stirred at 85-90°C for 15.0 hours and then quenched with 100 mL water, which resulted in a solid precipitate. The precipitate, which included F2A16 and impurities, was collected after centrifugation, washed twice with acetonitrile, and dissolved in 1U mL DMSO.
The DMSO
~s solution was then slowly added to 100 mL acetonitrile. The product, F2A16, in the form of a precipitate, was collected after centrifugation and then purified by SiOz TLC
until no hexadecaaniline [R~=0.7-0.75, THF-CHC13 ( 1:1 )-pyridine (one drop)] was detectable. The resulting blue solids were then dried under vacuum at 40°C to give 590 mg F2A16 in an 80%
yield.
2o F_ 2A, ~
1R (KBr) u"~: 3388 (br), 3035, 2933 (C-H), 2860, 1656 (amide), 1600, 1506 (s), 1300, 1172, 1123, 1044, 829, 751, 698, and 508 cm-'.
UV-Vis (1.5 x 10-6 M in DMSO) a,,nax~ 325 (benzenoid absorption) and 595 (quinonoid absorption) nm.
25 1H-NMR 8: 6.67 (m, 17H), 6.90 (m, 86H), 7.11 (m, 25H), and 7.75 (N-H, 8H, disappear in D20).

(4) Synthesis of fullerene deca(hexadecaaniline) (F10A,6) and dodeca(hexadecaaniline) (F12A16) adducts.
F10A16 and F12A~6 were prepared by the method as described in step (3) above, except that F10A and F12A were respectively used instead of F2A. The yields were 70-78%.
s F10A~
IR (KBr) um~: 3382 (br), 3280 (br), 3036, 2936 (C-H), 2865, 1648 (amide), 1600, 1504 (s), 1300, 1174, 1116, 828, ?51, 697, 619, and 509 cm'1.
UV-Vis (1.0 x 10'~ M in DMSO) ~.",~: 325 and 595 um.
lH-NMR S: 6.67 (m, 8H), 6.90 (m, 44H), 7.11 (m, 12H), and 7.6-7.8 (N-H, 4H, disappeared in DZO).
F 12A, ~
IR (KBr) umax~ 3387 (br), 3033 (br), 2931 (C-H), 2859, 1659 (amide), 1599, 1505 (s), 1298, 1171, 1128, 826, 750, 697, 636, and 507 cni 1.
UV-Vis (1.0 x 10~ M in DMSO) ~.~: 323 (benzenoid absorption) and 595 (quinonoid ~ 5 absorption) um.
1H-NMR 8: 6.67 (m, 8H), 6.94 (m, 44H), 7.11 (m, 12H), and 7.7-7.9 (N-H, 4H, disappear in D20).
Example 2.
2o Synthesis of sulfobutylated fullerene dodeca(hexadecaanilino)adduct (F12AI6S), deca(hexadecaanilino)adduct (F10A16S), and di(hexadecaanilino)adduct (F2A16S).
200 mg F12A16 and 15.0 mL DMF were added to a dry flask containing a stirring bar and a condenser under NZ. To the DMF solution were either sequentially added 1.0 mL
DBU, 0.5 mL 1,4-butane sultone, and stirred at 100°G for 12.0 hours or sequentially added 25 70 mg sodium hydride -30°C, stirred for 30 minutes, added 0.5 mL 1,4-butane sultone, and stirred at 60°C for 6,0 hours. It was then quenched with 100 mL dilute HCl-acetone solution to effect precipitation of a solid. The solid was collected after centrifugation, washed twice with acetonitrile, and dissolved in 15 mL DMSO-H20 (1:5) in the presence of 100 mg Na2C03. The DMSO-H20 solution was slowly added to acetone, resulting in precipitation of the product F12A16S. The product, in blue, was collected after centrifugation, washed with DMF and acetone, and then dried under vacuum at 40°C to yield 210-230 mg water-soluble F 12A~ 6S.
F12A,~S
IR (KBr) u",~: 3445 (br), 2944 (C-H), 2873, 1625 (amide, s), 1523, 1504, 1451, 1330, 1199 (s), 1044, 825, 729, 609, and 530 cm ~.
UV Vis (2.0 x 10-6 M in H20) ~."~: 328 (benzenoid absorption) and 605 (quinonoid absorption) nm.
1H-NMR (Dz0) b: 1.70 (m, 4H), 2.88 (t, 2H), 3.57 (t, 2H), and 7.0-7.8 (aromatic).
F2A16S and F10AI6S were prepared by the same method as described above, except that F2Ai6 and F10AI6 were respectively used.
F. 2A,~S
~5 IR (KBr) u~: 3442 (br), 2938 (C-H), 2873, 1622 (amide), 1605, 1506, 1417 (w), 1360 (w), 1183 (s), 1046, 827, 609, and 526 cm-~ .
F10A»S
IR (KBr) uT"~: 3427 (br), 2928 (C-H), 2859, 1647 (amide), 1598, 1503, 1317, 1171, 1039, 806, 606, and 518 cm'' .
2o 1H-NMR 8 (D20): 1.3-1.9 (4H), 2.7-2.9 (2H), 3.4-3.6 (2H), and 6.4-7.2 (aromatic).
Example 3 (1) Synthesis of F10A4 F10A4 was prepared by the method described in Example 1 (3), except that F10E
and 25 tetraaniline (A4) in the emeraldine base form were used instead of F2E and A16.
IR (KBr) u~: 3388 (br), 3030 (C-H), 2942 (C-H), 2810, 1601 (amide), 1506 (s), 1293, 1255, 1170, 820, 750, 696, and 506 crri 1.
to ............ . __.......~...,-.-,. ...._. .. ~.,~...._...

(2) Synthesis of sulfobutylated decaltetraanilino)-pentakis(methano)-[60]fullerene decacarbamide (F10A.~S).
80 mg F10A~ in 20 mL DMSO, and 60 mg sodium hydride were added into a dry flask equipped with a stirring bar and a condenser at ambient temperature under N~. The solution thus obtained was stirred for 30 minutes, followed by addition of 0.2 mL 1,4-butane sultone. The reaction mixture was slowly heated to 70°C and stirred for 12.0 hours, and was quenched with 100 mL dilute HCl-acetonitrile solution to effect precipitation.
The precipitate was collected after centrifugation, washed twice with acetonitrile, and dissolved in 10 mL HzO. The aqueous solution was then filtered through a celite filtering agent, and 1 o dried, to produce a blue precipitate. The blue precipitate was washed again with acetonitrile and dried under vacuum at 40°C to give 95 mg water-soluble FlOAaS.
IR (KBr) u""a,~: 3460 (br), 2945 (C-H), 2874, 1653 (amide, s), 1509, 1419 (w), 1186 (s), 1048 (s), 795, 611, and 533 cm-l.
'H-NMR 8 (D20): 1.2-1.9 (4H), 2.65-2.85 (2H), 3.2-3.5 (2H), and 6.3-7.0 (aromatic).
Example 4 In vitro irradiation-induced superoxide generation by F10A4S
F10A4S's ability to generate superoxide free radicals was demonstrated as follows:
1.0 mL 25 ~M F10AQS aqueous solution was added to 1.0 mL ferricytochrome C-containing 2o PBS (50 N,M). The solution thus obtained was added to each well of a 24-well plate, and exposed to fluorescence light source (27 watts) for 0-90 min. The distance between the plate cover and the light source was set at 5-6 cm. The extent of reduction of ferricytochrome C to ferrocytochrome C was evaluated by optical measurement. The increase of the absorbance at 550 nm corresponded to the increase of the quantity of ferrocytochrome C.
Production of ferrocytochrome C indicated that FlOAaS, upon irradiation, converted molecular oxygen by subsequent reactions to superoxide free radicals, and electron transfer from the superoxide free radicals to ferricytochrome C reduced the ferricytochrome C to ferrocytochrome C. The production of superoxide radicals was observed to increase systematically in a time-dependent manner with the irradiation time increasing from 0, 30, 60, to 90 minutes at a so constant F10A4S concentration of 25 ~M.

In a separate experiment, the presence of superoxide radicals in the solution was confirmed by selective removal of superoxide radicals with superoxide dismutase (SOD, 75 or 150 units). SOD effectively suppressed the irradiation-induced generation of superoxide radicals by F10A4S at 25 ~M for 90 minutes. The data confirm a linear correlation between the optical absorbance at S50 nm and the quantity of superoxide radicals produced by irradiation of F10A4S in the presence of molecular oxygen.
Example 5 In vitro irradiation-induced cytotoxicity of FIOAI6S based on tumor cell viability Two types of tumor cells were used in this study, and prepared as follows:
Fibrosarcoma cells (CCRC 60037) and sarcoma 180 cells (obtained form Biochemical Tnstitute of Chung Shan Medical and Dental College, Taiwan) were maintained and cultured in an a-modified eagle medium (MEM) containing L-glutamine and phenol red. It was supplemented with 10% fetal bovine serum and antibiotics (100 units/mL of penicillin G and ~5 100 p,g/mL streptomycin sulfate). The cells were incubated in the dark in 95% humidified air plus 5% CO2, and harvested by treatment with trypsin-EDTA. The harvested cells were suspended in an a MEM medium at the concentration of 1x104 cells per mL.
The cell suspension thus obtained was placed into wells of a 24-well plate (500 pL
each) and pre-incubated at 37°C for 24 hours. FlOAibS solutions at various concentrations 20 (0-10 pM) were then added to the wells (500 ~,L each). The wells were irradiated with fluorescence light (27 watts) for 0-60 minutes. The distance between the plate cover and the light source was set at 5-6 cm. After irradiation, the cells were further incubated for 48 hours. A solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT, 100 p.L, 0.5% in PBS, 100 L each) was then added to each of the wells to react with 25 mitochrondrial dehydrogenase in the living cells to produce formazon. Each cell suspension was again incubated at 37°C for 3 hours. The suspension medium was then discarded.
Formazon formed in cells from each well was then extracted with DMSO (1.0 mL
each).
The DMSO extract solution was immediately used for optical measurement. The absorbance at 540 nm was correlated with the quantity of formazon, and thus with the quantity of 3o dehydrogenase enzyme or the relative number of living cells (i.e., viability). The results show a decrease in cell viability in both dose-dependent and irradiation time-dependent manners. With an irradiation time of 60 minutes, a sharp loss of viable cells was observed when F10A16S concentration was increased from 2.5 to 5.0 pM. A maximal photodynamic cytotoxicity efficacy of >90% was obtained at an F10A16S concentration of 5.0-10.0 E,iM and an irradiation time of 60 minutes. In the absence of light irradiation, no cytotoxicity was observed even at the highest F10A16S concentration, i.e., 10 ~M. An ICSo of F10A16S of 2.9 uM was observed in irradiation treatment of the fibrosarcoma cells with an irradiation time of 60 minutes.
Example 6:
1 o In vivo photodynamic therapy study of F10A16S.
A photodynamic therapy study was conducted in male ICR mice (Charles River Japan origin Crl: CD-1~(ICR)BR). The mice were 8 weeks old, weighed 3710.8 g, housed in polycarbonated shoe-box cages on hardwood bedding (5 mice/cage) under controlled conditions (temperature 2211°C, relative humidity 5515%, and light/dark cycle 12/12 15 hours), and allowed free access to a laboratory rodent diet (# SK55, Purina Mills, Inc., St.
Louis, MO) and water.
Marine sarcoma 180 cells were maintained by transplantation to other mice in the abdominal cavity biweekly. Subcutaneous tumors were induced by intraperitoneal injection of 1x10' tumor cells (about 0.1-0.15 ml ascitic fluid) to the subcutaneous region of 2o abdominal cavities of the mice for this study, and were allowed to proliferate at the inoculation sites for S-7 days until they reached a size with a diameter of 102 mm. Thirty tumor-bearing mice were divided into 3 groups, including (a) tumor control, (b) intraperitoneal injection of F10A16S (10 mg/kg) to tumor-bearing mice followed by laser irradiation at 514 nm, and (c) intraperitoneal injection to F10A16S (10 mg/kg) on tumor-2s bearing mice followed by laser irradiation at 633 nm.
Each mouse in groups (b) and (c) was intraperitoneally injected with F10A,6S
in PBS
at a site roughly 2.0 cm away from the tumor location, kept in the dark for 24 hours to allow bio-distribution of F10A~6S to the tumor site, and then anesthetized by avertine (0.3 mL/head). The tumor site in each mouse in groups (b) and (c) was exposed by removing the 3o hair on and around it, and then subsequently irradiated with an argon ion laser beam (Spectra Physics, Model 168) at a wavelength of 514 or 633 nm. The beam was delivered via a quartz fiber with the circular area of illumination output focused to a diameter of 7-8 mm with the total light dose adjusted to a level of 100 J/cm2 in each experiment.
After the treatment, the mouse was examined every 5 days for 30 days. Efficacy of the irradiation therapy was evaluated by measuring the body weights and tumor volumes of the mouse. At day 30, the mice were euthanatized by carbon dioxide asphyxiation, and the weights of the body, liver, kidney, spleen, heart, and tumor, were measured.
Blood samples were withdrawn, and plasma biochemistry and blood hematology analyses were conducted with a Hitachi 7050 Automatic Analyzer and a Serono System 9000, respectively.
All of the irradiation-treated mice showed sharp decreases in the weights of the 1o isolated tumors. At the Fl0At6S concentration of 10 mg/kg, the tumor weight in the mice of group (b), i.e., irradiated at 514 nrn, reached roughly 60% less than that of the tumor control group. At the same F10A16S concentration, the tumor weight in the mice of group (c), i.e., irradiated at 633 nm, was nearly 99% less than that of the tumor control group. These results indicated an unexpectedly high efficacy of F10A16S on reducing the viability and ~ 5 proliferation of fibrosarcoma tumor cells in photodynamic therapy.
OTHER EMBODIMENTS
A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and 2o scope of the invention. For example, the oligoanilinated fullerenes can be used as photoactivated biocidal agents, or drugs capable of forming multi-covalent bonds with a target. Accordingly, other embodiments are within the scope of the following claims.

Claims (33)

1. A compound of the following formula:

wherein p and each q, independently, is an integer of 0-20;
each a is an integer of 1-8;
each b is 0 or 1;
each c is an integer of 1-20, provided that when b is 0, c is 1;
each n is 1 or 2;
m is an integer of 1-20;
F1 and each F2, independently, is a fullerene;
each of S and T, independently, is -OH,-NH2, -NHR, or -SH, wherein R being C1-30 alkyl;
each A, independently, is an oligoaniline, wherein each nitrogen atom is optionally substituted with -Z, -CH2-CO-OH, -CH2-CO-O-Z, -CH2-CO-S-Z, -CH2-CO-NH2, or -CH2-CO-NH-Z; each benzene ring is optionally substituted with -O-Z, -S-Z, -NH-Z; Z being -E-D, wherein E is -R-, -R-Ar-, -Ar-R-, or -Ar-; and D is -OH, -SH, -NH2, -NHOH, -SO3H, -OSO3H, -CO2H, -CONH2, -CH-(NH2)-CO2H, -P(OH)3, -PO(OH)2, -O-PO(OH)2, -O-PO(OH)-O-PO(OH)2, -O-PO(O-)-O-CH2CH2NH3+, -glycoside, -OCH3, -OCH2(CHOH)4-CH2OH, -OCH2(CHOH)2-CH2OH, -C6H3(OH)2, -NH3+, -N+H2R b, -N+HR b R c, or -N+R b R c R d, R being C1-30 alkyl; each of R b, R c, and R d, independently, being C1-20 alkyl; and Ar being aryl;
each K, independently, is -H, -[N(X)-C6H4]1-3-NH2, -[N(X)-C6H4]1-3-NH-C(=S)-SH, -[N(X)-C6H4]1-3-N=CH-Ar-SH, -[N(X)-C6H4]1-3-NH-CO-Ar-SH, wherein X is -H, -Z, -CH2-CO-OH, -CH2-CO-O-Z, -CH2-CO-S-Z, -CH2-CO-NH2, -CH2-CO-NH-Z; and Ar is aryl;
each G, independently, is -O-B-R-O-, -NH-B-R-NH-, -O-B-R-NH-, -NH-B-R-O-, -O-B-R-S-, -NH-B-R-S-, wherein R is C1-30 alkyl; B, independently, is -R1-O-[Si(CH3)2-is O-]1-100, C1-2000 alkyl, C6-40 aryl, C7-60 alkylaryl, C7-60 arylalkyl, (C1-30 alkyl ether)1-100, (C6-40 aryl ether)1-100, (C7-60 alkylaryl ether)1-100, (C7-60 arylalkyl ether)1-100, (C1-30 alkyl thioether)1-100, (C6-40 aryl thioether)1-100, (C7-60 alkylaryl thioether)1-100, (C7-60 arylalkyl thioether)1-100, (C2-50 alkyl ester)1-100, (C7-60 aryl ester)1-100, (C8-70 alkylaryl ester)1-100, (C8-70 arylalkyl ester)1-100, -R1-CO-O-(C1-30 alkyl ether)1-100, -R1-CO-O-(C6-40 aryl ether)1-100, -R1-CO-O-(C7-60 alkylaryl ether)1-100, -R1-CO-O-(C7-60 arylalkyl ether)1-100, (C4-50 alkyl urethane)1-100, (C14-60 aryl urethane)1-100, (C10-80 alkylaryl urethane)1-100, (C10-80 arylalkyl urethane)1-100, (C5-50 alkyl urea)1-100, (C14-60 aryl urea)1-100, (C10-80 alkylaryl urea)1-100, (C10-80 arylalkyl urea)1-100, (C2-50 alkyl amide)1-100, (C7-60 aryl amide)1-100, (C8-70 alkylaryl amide)1-100, (C8-70 arylalkyl amide)1-100, (C3-30 alkyl anhydride)1-100, (C8-50 aryl anhydride)1-100, (C9-60 alkylaryl anhydride)1-100, (C9-60 arylalkyl anhydride)1-100, (C2-30 alkyl carbonate)1-100, (C7-50 aryl carbonate)1-100, (C8-60 alkylaryl carbonate)1-100, (C8-60 arylalkyl carbonate)1-100, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100-R3-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100-R3O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-NH-(C2-50 alkyl amide, C7-60 aryl amide, C8-70 alkylaryl amide, or C8-70 arylalkyl amide)1-100, or -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-NH-(C2-50 alkyl amide, C7-60 aryl amide, C8-70 alkylaryl amide, or C8-70 arylalkyl amide)1-100;
wherein each of R1, R2, and R3, independently, is C1-30 alkyl; and Ar is aryl.

2. The compound of claim 1, wherein a is an integer of 2-6.

3. The compound of claim 1, wherein b is 0; and c is 1.

4. The compound of claim 1, wherein n is 2.

5. The compound of claim 2, wherein b is 0; and c is 1.

6. The compound of claim 2, wherein a is 4.

7. The compound of claim 2, wherein n is 2.

8. The compound of claim 6, wherein b is 0; and c is 1.

9. The compound of claim 6, wherein n is 2.

10. The compound of claim 8, wherein n is 2.

11. The compound of claim 3, wherein n is 2.

12. The compound of claim 1, wherein A is tetraaniline, optionally substituted at one or more nitrogen atoms with Z; E is -R- or -R-Ar-; and D is -OH, -SH, -NH2, -NHOH, -SO3H, -OSO3H, -CO2H, -CONH2, -P(OH)3, -PO(OH)2, -O-PO(OH)2, -O-PO(OH)-O-PO(OH)2, or -NH3+.

13. The compound of claim 12, wherein A is tetraaniline of the emeradine base form, substituted at the nitrogen atoms of the benzenoid units with -C3H6SO3Na or -C4H8SO3Na.

14. The compound of claim 12, wherein a is an integer of 2-6.

15. The compound of claim 12, wherein b is 0; and c is 1.

16. The compound of claim 12, wherein n is 2.

17. The compound of claim 13, wherein a is an integer of 2-6.

18. The compound of claim 13, wherein b is 0; and c is 1.

19. The compound of claim 13, wherein n is 2.

20. The compound of claim 17, wherein a is 4.

21. The compound of claim 20, wherein b is 0; c is 1; and n is 2.

22. The compound of claim 21, wherein m is an integer of 1-8.

23. The compound of claim 22, wherein F1 is C60 fullerene; K is H; and p is 0.

24. The compound of claim 18, wherein n is 2.

25. The compound of 14, wherein b is 0; and c is 1.

26. The compound of claim 14, wherein n is 2.

27. The compound of claim 15, wherein n is 2.

28. The compound of claim 1, wherein b is 1.

29. A pharmaceutical composition, comprising a compound of the following formula:

wherein p and each q, independently, is an integer of 0-20;
each a is an integer of 1-8;
each b is 0 or 1;
each c is an integer of 1-20, provided that when b is 0, c is 1;
each n is 1 or 2;
m is an integer of 1-20;
F1 and each F2, independently, is a fullerene;
each of S and T, independently, is -OH,-NH2, -NHR, or -SH, wherein R being C1-30 alkyl;
each A, independently, is an oligoaniline, wherein each nitrogen atom is optionally substituted with -Z, -CH2-CO-OH, -CH2-CO-O-Z, -CH2-CO-S-Z, -CH2-CO-NH2, or -CH2-CO-NH-Z; each benzene ring is optionally substituted with -O-Z, -S-Z, -NH-Z; Z being -E-D, wherein E is -R-, -R-Ar-, -Ar-R-, or -Ar-; and D is -OH, -SH, -NH2, -NHOH, -SO3H, -OSO3H, -CO2H, -CONH2, -CH-(NH2)-CO2H, -P(OH)3, -PO(OH)2, -O-PO(OH)2, -O-PO(OH)-O-PO(OH)2, -O-PO(O-)-O-CH2CH2NH3+, -glycoside, -OCH3, -OCH2(CHOH)a-CH2OH, -OCH2(CHOH)2-CH2OH, -C6H3(OH)2, -NH3+, -N+H2R b, -N+HR b R c, or -N+R b R c R d, R being C1-30 alkyl; each of R b, R c, and R d, independently, being C1-20 alkyl; and Ar being aryl;
each K, independently, is -H, -[N(X)-C6H4]1-3-NH2, -[N(X)-C6H4]1-3-NH-C(=S)-SH, -[N(X)-C6H4]1-3-N=CH-Ar-SH, -[N(X)-C6H4]1-3-NH-CO-Ar-SH, wherein X is -H, -Z, -CH2-CO-OH, -CH2-CO-O-Z, -CH2-CO-S-Z, -CH2-CO-NH2, -CH2-CO-NH-Z; and Ar is aryl;
each G, independently, is -O-B-R-O-, -NH-B-R-NH-, -O-B-R-NH-, -NH-B-R-O-, -O-B-R-S-, -NH-B-R-S-, wherein R is C1-30 alkyl; B, independently, is -R1-O-[Si(CH3)2-O-]1-100, C1-2000 alkyl, C6-40 aryl, C7-60 alkylaryl, C7-60 arylalkyl, (C1-30 alkyl ether)1-100, (C6-40 aryl ether)1-100, (C7-60 alkylaryl ether)1-100, (C7-60 arylalkyl ether)1-100, (C1-30 alkyl thioether)1-100, (C6-40 aryl thioether)1-100, (C7-60 alkylaryl thioether)1-100, (C7-60 arylalkyl thioether)1-100, (C2-50 alkyl ester)1-100, (C7-60 aryl ester)1-100, (C8-70 alkylaryl ester)1-100, (C8-70 arylalkyl ester)1-100, -R1-CO-O-(C1-30 alkyl ether)1-100, -R1-CO-O-(C6-40 aryl ether)1-100, -R1CO-O-(C7-60 alkylaryl ether)1-100, -R1-CO-O-(C7-60 arylalkyl ether)1-100, (C4-50 alkyl urethane)1-100, (C14-60 aryl urethane)1-100, (C10-80 alkylaryl urethane)1-100, (C10-80 arylalkyl urethane)1-100, (C5-50 alkyl urea)1-100, (C14-60 aryl urea)1-100, (C10-80 alkylaryl urea)1-100, (C10-80 arylalkyl urea)1-100, (C2-50 alkyl amide)1-100, (C7-60 aryl amide)1-100, (C8-70 alkylaryl amide)1-100, (C8-70 arylalkyl amide)1-100, (C3-30 alkyl anhydride)1-100, (C8-50 aryl anhydride)1-100, (C9-60 alkylaryl anhydride)1-100, (C9-60 arylalkyl anhydride)1-100, (C2-30 alkyl carbonate)1-100, (C7-50 aryl carbonate)1-100, (C8-60 alkylaryl carbonate)1-100, (C8-60 arylalkyl carbonate)1-100, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100-R3-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C1-30 alkyl ether, C6-40 aryl ether, C7-60 alkylaryl ether, or C7-60 arylalkyl ether)1-100-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-(C2-50 alkyl ester, C7-60 aryl ester, C8-70 alkylaryl ester, or C8-70 arylalkyl ester)1-100-R3O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-O-, -R1-O-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-NH-(C2-50 alkyl amide, C7-60 aryl amide, C8-70 alkylaryl amide, or C8-70 arylalkyl amide)1-100, or -R1-NH-CO-NH-(R2 or Ar-R2-Ar)-NH-CO-NH-(C2-50 alkyl amide, C7-60 aryl amide, C8-70 alkylaryl amide, or C8-70 arylalkyl amide)1-100;
wherein each of R1, R2, and R3, independently, is C1-30 alkyl; and Ar is aryl;
and a pharmaceutically acceptable carrier.

30. The pharmaceutical composition of claim 29, wherein a is an integer of 2-6.

31. The composition of claim 30, wherein b is 0; c is 1; and n is 2.

32. The composition of claim 31, wherein p is 0; a is 4; m is an integer of 1-8; F1 is C60 fullerene; and A is tetraaniline of the emeradine base form, substituted at the nitrogen atom of each benzenoid unit with -C3H6SO3Na or -C4H8SO3Na.

33. The composition of claim 29, wherein b is 1.